Activation of lung myofibroblasts (LMF) of different origins is responsible for the development of lung fibrosis in in IPF and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. Inhibiting or reversing myofibroblast activation and macrophage activation (the therapeutic cellular targets) may be critical for the treatment of lung fibrosis in IPF. Both preventing progression of lung fibrosis and inflammation, as well as possibly, regression of lung fibrosis despite continued lung injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with IPF. Finally, blocking the progression of lung fibrosis may decrease the demand for lung transplants. The basis for our Research is the development of a novel ?humanized? therapeutic peptide. We created a library using analog synthesis to prevent potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient ?humanized? peptide (including apoptosis assays in activated primary human lung myofibroblasts; cell-free caspase 8 activation assays; lung injury/fibrogenesis model; pharmacokinetics; bioassay; CYP-450 inhibition studies; cardiotoxicity assays; and preliminary toxicology assays). We have developed novel and highly effective anti-fibrotic peptides in animal models, with no evidences of immunogenicity in state-of-the-art human CD-4+ T-cell and B- cell assays, and with exceptional stability in human lung microsomal systems and human plasma. The therapeutic peptide has excellent solubility in water. These features should facilitate administration by subcutaneous injection once per week (~ 50-200 ?L) with excellent bioavailability during preclinical PK studies judging by the steady-state release in plasma of the peptide from the PEG-30kDa-Peptide, achieving therapeutic lung concentrations. Xfibra will maintain the inhalation route as an alternative formulation for development. The proposed compound markedly inhibits the activation of human lung myofibroblast in culture and in vivo in mice. This compound was not toxic to mice in the preliminary toxicology studies, at least at 100- fold the therapeutic dose. We found no evidence of liver, lung or cardiac toxicity or inhibition of CYP-450 isoenzymes. The Aims of this SBIR are to complete FDA-mandated, IND-enabling studies. The available IPF medications are very expensive, and not highly effective in most patients. The FDA agreed with Xfibra to proceed with IND-enabling studies for XFB-19 (Pre-IND # 131245).